Results of a phase I trial of KX2–391, a novel non-ATP competitive substrate-pocket directed SRC inhibitor, in patients with advanced malignancies

Abstract

3511 Background: Src kinase is central to the proliferation, apoptosis and metastasis of tumor cells. KX2–391 is a synthetic, orally bioavailable small molecule Src tyrosine kinase signaling inhibitor. KX2–391 is distinct from all other known Src kinase inhibitors in targeting the peptide substrate-binding site and not the ATP-binding site. KX2–391 is the first peptide site targeted tyrosine kinase inhibitor to enter clinical trials. KX2–391 has a much wider spectrum of solid tumor activity in vitro, and is more potent in mouse xenografts, as compared to other multikinase Src/Abl inhibitors. Methods: This multi-center Phase 1 trial utilized the standard 3+3 design to determine the Maximum Tolerated Dose (MTD), safety, and pharmacokinetics (PK) of KX2–391 in pts with refractory solid tumors. Results: To date, 32 pts (12 m 20 f, median age 59 (range 31–78)) have been enrolled in 7 dose cohorts. Dose limiting toxicities (DLTs), which were all reversible within 7 days, occurred in 4 pts and included elevated ALT and AST, neutropenia, and fatigue. 22 pts experienced no Grade 3 or 4 adverse events. Other Grade 1/2 adverse events include: hypokalemia, anemia, elevated AST, fatigue, dyspnea, fever, vomiting, constipation, hematuria, and lymphopenia. The MTD is 40 mg BID on a 3 out of 4 weeks dosing schedule. 7 pts had prolonged stable disease for 4 months or longer including 2 pts with papillary thyroid carcinoma, 2 with carcinoid, and 1 each with prostate, pancreas, and head and neck cancer. Both the prostate and pancreatic cancer pts had dramatic decreases in their biomarkers (PSA went from 205 ng/ml to 39 ng/ml, and CA19–9 went from 38,838 U/ml to 267 U/ml, respectively). The PK profile demonstrated dose-proportionality, a half-life of 4.5 hrs and a Tmax of 1 hr with no evidence of accumulation with multiple doses. Conclusions: KX2–391 has a favorable PK profile, is well-tolerated, demonstrates preliminary evidence of biologic activity and should be further evaluated in Phase II trials. [Table: see text] [Table: see text]